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Centenarian Exome Analysis Points to Conserved Longevity Pathways

NEW YORK – Rare protein-coding variants in pathways linked to longevity in nonhuman model organisms appear to guard against common, age-related conditions in exceptionally long-lived individuals, according to new research from a team based in the US, Italy, Germany, and Israel.

"Rare variants in aging pathways affect human lifespan and constitute a part of the genetic architecture of human longevity," corresponding author Zhengdong Zhang, a genetics researcher at the Albert Einstein College of Medicine, explained in an email, adding that "effects of pathogenic rare variants on human lifespan are dependent on the background of common polygenic risk of age-related diseases."

For their rare variant association study, published in Nature Aging on Monday, Zhang and colleagues sequenced the exomes of 515 centenarians of Ashkenazi Jewish ancestry and 496 non-centenarian controls between around 70 and 95 years of age, uncovering nearly 130,300 rare SNPs or small insertions or deletions that were considered for association analyses. They noted that the non-centenarian study participants came from the same households as the centenarians in many cases, but did not have a family history of relatives living past the age of 95.

"Identifying rare genetic variants enriched in centenarians and possibly related to their extreme longevity with large effect sizes could be a key strategy to develop the drug targets desperately needed for combating age-related multimorbidity," Zhang said. "This study is our first step toward developing new therapies to extend the human health span."

The proportion of rare pathogenic variants was comparable in the centenarian and non-centenarian participants. But the team noted that the rare variants found in those living at least 100 years were overrepresented in specific pathways that have been linked to longevity in past studies of model organisms such as mice, fruit flies, or nematode worms, suggesting those variants may contribute to long life across species.

"Centenarians have a number of pathogenic rare coding variants similar to control individuals, suggesting that rare variants detected in the conserved longevity pathways are protective against age-related pathology," the authors wrote.

The investigators saw an uptick in rare variants centered on insulin and insulin-like growth factor 1 signaling in the centenarians, for instance, along with signaling pathways linked to AMP-activating protein kinase enzyme activity — results they validated using data for thousands more centenarians and non-centenarians from three more population cohorts.

To further delve into such findings, the researchers considered rare variant interactions with potentially pathogenic variants or with common variants contributing to polygenic risk scores for several common age-related diseases such as type 2 diabetes, coronary artery disease, and certain cancer types.

When they searched for rare variants that appeared to protect against common age-related diseases, they uncovered rare Wnt signaling pathway variants in the centenarians that appeared to protect against the negative effects of APOE4 gene alleles linked to Alzheimer's disease and other conditions.

"[W]e detected a pro-longevity effect of rare coding variants in the Wnt signaling pathway among long-lived individuals harboring APOE4, a well-known common risk gene variant associated with Alzheimer's disease, hyperlipidemia, atherosclerosis, and a shorter life expectancy," Zhang said.

The study authors suggested the results may eventually lead to promising targets for extending life and warding off some age-related conditions, though they cautioned that additional studies, including long-read genome sequencing analyses, are needed to search for potential longevity contributors in non-coding portions of the genome.

"A limitation of [whole-exome sequencing], as used in our present study, is the absence of rare, non-coding variants that have been implicated in aging of model organisms and that are thus of potential interest regarding human longevity," the authors concluded. "These include, for example, rare variants in non-coding RNAs or other regulatory elements relevant for tissue specificities, and variants in long tandem repeats connected to brain health and various neurological disorders."

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